Triazine compounds of formula I, as defined below, and their pharmaceutically acceptable salts, lower fructose levels in the tissues of mammals affected by diabetes (e.g., nerve, kidney and retina tissue) and are useful in the treatment and prevention of the diabetic complications referred to above. These compounds, and/or their metabolites in vivo, are inhibitors of the enzyme sorbitol dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.
Commonly assigned U.S. Pat. Nos. 5,728,704 and 5,866,578 disclose compounds of formula A wherein R1 through R5 are defined as disclosed therein, which are useful as sorbitol dehydrogenase inhibitors, having utility in the treatment of diabetic complications. Commonly assigned International Publication No. WO 00/59510 discloses aminopyrimidines as sorbitol dehydrogenase inhibitors. Commonly assigned published European Patent Application EP 1 041 068 discloses pyrimidine derivatives as sorbitol dehydrogenase inhibitors, useful for treating or preventing diabetic complications.
Commonly assigned U.S. non-provisional Ser. No. 09/974,414, filed Oct. 9, 2001, discloses pharmaceutical combinations of statins and sorbitol dehydrogenase inhibitors. Commonly assigned U.S. non-provisional Ser. No. 09/997,039, filed, Nov. 29, 2001, discloses the combination of a γ-aminobutyric acid (GABA) agonists and sorbitol dehydrogenase inhibitors.
U.S. Pat. Nos. 5,138,058 and 5,215,990 disclose piperazine substituted pyrimidine compounds, having utility as tools in screening for aldose reductase inhibitors due to the sorbitol accumulating activity of said compounds.